Combination therapy using ribavirin as elF4E inhibitor

Abstract

The present invention relates to pharmaceutical compositions and combination therapies for treating patients having a neoplasm or a proliferative disorder, the combination comprises ribavirin, GDC-0449 and a chemotherapeutic agent, wherein said combination therapy overcomes resistance developed in patients during anti-neoplastic treatment. The present invention also provides a combination therapy for treating patients having leukemia.

The invention claimed is: 
     
       1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of ribavirin and GDC-0449 in the form of a combined preparation. 
     
     
       2. The pharmaceutical composition according to  claim 1 , further comprising a therapeutically effective amounts of a chemotherapeutic agent. 
     
     
       3. The pharmaceutical composition according to  claim 2 , wherein the chemotherapeutic agent is cytarabine. 
     
     
       4. The pharmaceutical composition according to  claim 1 , wherein the therapeutically effective amounts of ribavirin is between about 1000 and about 4400 mg per day. 
     
     
       5. The pharmaceutical composition according to  claim 3 , wherein the pharmaceutical composition comprises a low dose of cytarabine. 
     
     
       6. The pharmaceutical composition according to  claim 5 , wherein the low dose of cytarabine ranges from about 10 mg per day to about 20 mg twice a day. 
     
     
       7. The pharmaceutical composition according to  claim 5 , wherein the low dose of cytarabine ranges from about 5 μM to about 15 μM per day. 
     
     
       8. The pharmaceutical composition according to  claim 1 , wherein said composition is suitable for inhalation, ocular administration, nasal instillation, parenteral administration, dermal administration, transdermal administration, buccal administration, rectal administration, sublingual administration, perilingual administration, nasal administration, topical administration or oral administration. 
     
     
       9. A method for the treatment of leukemia comprising: administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of GDC-0449. 
     
     
       10. The method according to  claim 9 , further comprising administering a therapeutically effective amounts of a chemotherapeutic agent. 
     
     
       11. The method according to  claim 10 , wherein the chemotherapeutic agent is cytarabine. 
     
     
       12. The method according to  claim 9 , wherein ribavirin and GDC-0449 are separately, sequentially or simultaneously co-administered. 
     
     
       13. The method according to  claim 11 , wherein the therapeutically effective amounts of ribavirin and GDC-0449 are separately, sequentially or simultaneously co-administered prior to administration of the cytarabine. 
     
     
       14. The method according to  claim 13 , wherein the method comprises administering ribavirin and GDC-0449 in a single unit dosage form. 
     
     
       15. The method according to  claim 9 , wherein the ribavirin is administered in an amount between 1000 and 4400 mg per day. 
     
     
       16. The method according to  claim 11 , wherein the cytarabine is administered in a low dose. 
     
     
       17. The method according to  claim 16 , wherein the low dose ranges from about 10 mg per day to about 20 mg twice a day. 
     
     
       18. The method according to  claim 16 , wherein the low dose of cytarabine ranges from about 5 μM to about 15 μM per day. 
     
     
       19. The method according to  claim 10 , wherein the chemotherapeutic agent is administered in an amount up to 100 mg/m 2  per day, for up to 7 days every 4 weeks. 
     
     
       20. The method according to  claim 12 , wherein the therapeutically effective amount of GDC-0449 ranges from about 3 μM for two days prior to start of administration of the ribavirin. 
     
     
       21. The method according to  claim 9 , wherein the leukemia is selected from the group consisting of: acute myeloid leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and myelodysplastic syndromes. 
     
     
       22. The method according to  claim 21 , wherein the acute myeloid leukemia is selected from the group consisting of: acute myeloid leukemia M4, acute myeloid leukemia M5 and AML subtypes characterized by atypical elevation of the e1F4E gene product. 
     
     
       23. The method according to  claim 14 , wherein said composition is suitable for inhalation, ocular administration, nasal instillation, parenteral administration, dermal administration, transdermal administration, buccal administration, rectal administration, sublingual administration, perilingual administration, nasal administration, topical administration or oral administration. 
     
     
       24. The method according to  claim 9 , comprising administering a therapeutically effective amount of GDC-0449 in the presence of a therapeutically effective amount of ribavirin, wherein the resistance previously developed in patients during anti-leukemia treatment is minimized by the reduction of UGT1A proteins levels and inhibition of the Gli-1 overexpression. 
     
     
       25. The method according to  claim 9 , wherein the ribavirin and GDC-0449 are administered orally. 
     
     
       26. The method according to  claim 14 , wherein said single unit dosage form is administered orally. 
     
     
       27. A combination comprising a first pharmaceutical composition including a pharmaceutically acceptable carrier and a therapeutically effective amount of ribavirin and a second pharmaceutical composition including a pharmaceutically acceptable carrier and a therapeutically effective amount of GDC-0449.